Neutralizing antibodies are important effectors in humoral immune responses against bacterial or viral infections, including HIV. However, it is difficult to elicit effective neutralizing antibody responses against HIV in natural infections or y conventional vaccine approaches. Previous studies of HIV viral genome and envelop protein structures have suggested that HIV has evolved many strategies to avoid neutralizing antibody responses. Recent studies of neutralizing antibodies and anti-gp120 antibodies derived from HIV elite controllers showed that most of these antibodies are polyreactive, which are not generally tolerated during B cell development. VH replacement is normally considered as a receptor editing mechanism to change non- functional IgH genes or IgH genes encoding autoreactive antibodies. We found that VH replacement products are highly enriched in IgH genes derived from plasmablasts of HIV patients and the majority of these accumulated VH replacement products encode anti-gp120 and polyreactive antibodies. Moreover, treatment of EU12 mHC+ cells with gp120 proteins induces Ca++ influx in a BCR dependent manner and also induces VH replacement. Based on these results, we hypothesize that persistent HIV gp120 antigens induce VH replacement in the immature B cells in HIV infected patients; the resulting mature B cells expressing VH replacement products are positively selected later during anti-HIV response to generate anti-HIV and self/polyreactive antibodies. To test this hypothesis, (1) we will determine if VH replacement products are enriched in HIV patients; (2) we will determine if the accumulated VH replacement products encode anti-HIV and self/polyreactive antibodies; (3) we will determine if VH replacement is induced in the immature B cells of HIV patients and determine if gp120 induces VH replacement in human immature B cells. We will further determine if modulation of BCR signaling enhances gp120 induced VH replacement. Induction of VH replacement in the immature B cells and positive selection of mature B cells expressing VH replacement products during anti-HIV response are two different processes triggered by HIV viral antigens during chronic HIV infection. Understanding the underlying mechanisms will allow us to regulate VH replacement and facilitate the generation of effective anti-HIV antibodies in future vaccine design.